COL25A1

protein-coding

collagen type XXV alpha 1 chain, the group of Collagens

Gene summary

This gene encodes a brain-specific membrane associated collagen. A product of proteolytic processing of the encoded protein, CLAC (collagenous Alzheimer amyloid plaque component), binds to amyloid beta-peptides found in Alzheimer amyloid plaques but CLAC inhibits rather than facilitates amyloid fibril elongation (PMID: 16300410). A study of over-expression of this collagen in mice, however, found changes in pathology and behavior suggesting that the encoded protein may promote amyloid plaque formation (PMID: 19548013). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

MANE transcript

NM_198721.4

Inheritance

AR, AD

ClinVar variants

P:10U:94B:26

Top phenotype

Fibrosis of extraocular muscles, congenital 5

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr4:108,808,725-109,302,752

External References & Databases

Ensembl (ENSG00000188517)

Transcript & Mutation Effects

hg38 • Region Span ~494.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fibrosis of extraocular muscles, congenital, 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014538

Submitter: Ambry Genetics

fibrosis of extraocular muscles, congenital, 5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014538

Submitter: Genomics England PanelApp

fibrosis of extraocular muscles, congenital, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014538

Submitter: Labcorp Genetics (formerly Invitae)

congenital ptosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008340

Submitter: Orphanet

fibrosis of extraocular muscles, congenital, 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014538

Submitter: G2P

Clinical Genomic Database (CGD)

Fibrosis of extraocular muscles, congenital 5AR

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 25500261

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COL25A1 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 84

not providedTotal: 38

COL25A1-related disorderTotal: 19

Fibrosis of extraocular muscles, congenital, 5Total: 12

not specifiedTotal: 2

ArthrogryposisTotal: 1

Arthrogryposis multiplex congenitaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_198721.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	18 clinvar	3 clinvar	23
missense	1 clinvar	2 clinvar	89 clinvar	4 clinvar	1 clinvar	97
nonsense	2 clinvar	1 clinvar				3
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)		3 clinvar	3 clinvar			6
Total	4	6	94	22	4	130

Highest pathogenic variant AF is 0.0000068433837

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_198721.4	RefSeq	NP_942014.1	37	MANE Select
ENST00000399132.6	Ensembl	ENSP00000382083.1	37	MANE Select
NM_001256074.3	RefSeq	NP_001243003.1	33	Standard
NM_032518.4	RefSeq	NP_115907.2	34	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Collagen chain trimerization
Collagen biosynthesis and modifying enzymes
Collagen degradation
Collagen formation
Extracellular matrix organization

Biological Process

extracellular matrix organization
axonogenesis involved in innervation

Molecular Function

amyloid-beta binding
extracellular matrix structural constituent
heparin binding

Cellular Component

extracellular region
collagen trimer
extracellular space
endoplasmic reticulum lumen
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000399132
Coding exons: 36
Length: 491937
Individuals with no LoFs: 124729
Homozygous LoFs: 0
Heterozygous LoFs: 70
Defined: 124799
p: 0.000280

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.45	301	381	0.791	0.0000196	4101
Missense (PolyPhen)		88	134.52	0.65416		1382
Synonymous	0.0380	126	127	0.996	0.00000677	1346
Loss of Function	2.30	37	55.5	0.667	0.00000270	668

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00039	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00017	rare
Finnish	0.00019	0.00019	rare
European (Non-Finnish)	0.00032	0.00032	rare
South Asian	0.00050	0.00049	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Inhibits fibrillization of amyloid-beta peptide during the elongation phase. Has also been shown to assemble amyloid fibrils into protease-resistant aggregates. Binds heparin. {ECO:0000269|PubMed:15522881, ECO:0000269|PubMed:15615705, ECO:0000269|PubMed:15853808, ECO:0000269|PubMed:16300410}.;
Disease: DISEASE: Fibrosis of extraocular muscles, congenital, 5 (CFEOM5) [MIM:616219]: An ocular motility disorder characterized by congenital dysinnervation of various cranial nerves to ocular muscles. Clinical features are ophthalmoplegia, anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. {ECO:0000269|PubMed:25500261}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.164
RVIS EVS: -0.36
RVIS percentile EVS: 29.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.468

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium